This invention relates to methods and compositions for treating diseases that alter the surface active properties of the lung. An important feature in all mammalian lungs is the presence of surface active lining material in the alveoli. These surface active materials are lung surfactants comprised of protein-lipid compositions, e.g. surface active proteins and phospholipids, which are produced naturally in the lungs and are essential to the lungs' ability to absorb oxygen. They facilitate respiration by continually modifying surface tension of the fluid normally present within the air sacs, or alveoli, that line the inside of the lungs. In the absence of sufficient lung surfactant or when lung surfactant functionality is compromised, these air sacs tend to collapse, and, as a result, the lungs do not absorb sufficient oxygen.
Insufficient or dysfunctional surfactant in the lungs results in a variety of respiratory illnesses in both infants and adults. For example, insufficient lung surfactant may manifest itself as respiratory distress syndrome in premature infants (“iRDS”), i.e. those born prior to 32 weeks of gestation, who have not fully developed a sufficient amount of natural lung surfactant. Diseases involving dysfunctional lung surfactant include may adult respiratory disorders such as acute respiratory distress syndrome (ARDS), asthma, pneumonia, acute lung injury (ALI), etc., as well as infant diseases such as meconium aspiration syndrome (MAS), wherein full-term babies have their first bowel movement in the womb and aspirate the meconium into their lungs. In these cases, the amount of lung surfactant may be normal, but surfactant properties have been disrupted by foreign matter, trauma, sepsis and other infection, etc.
Diseases involving surfactant deficiency and dysfunction have historically been treated by the administration of surface active materials to the lungs, sometimes referred to as surfactant (replacement) therapy. For example, surfactant therapy is at present an established part of routine clinical management of newborn infants with iRDS. Usually these surface active materials are naturally-occurring or synthetically engineered lung surfactants, but may also be nonphospholipid substances such as perfluorocarbons. As used herein, the terms “lung surfactant” and “surfactant” contemplate all of these service active materials suitable for use in surfactant therapy. These lung surfactants can be administered in a variety of ways, the simplest being direct instillation of a liquid solution of lung surfactant into the lungs. An initial dose of about 100 mg/kg body weight (BW) is usually needed to compensate for the deficiency of lung surfactant in these babies, and repeated treatment is required in many cases.
An alternative approach is treatment with aerosolized lung surfactant. Aerosol delivery of surfactant to the lungs is usually less efficient than direct instillation, mainly because of large losses of aerosol in the delivery system. In conventional delivery systems, the amount of aerosol reaching the lungs can be further reduced if particle sizes are too large, i.e. >5 μm mass median aerodynamic diameter (MMAD), if aerosol delivery is not coordinated with slow inspiration and breath-hold, or if airways (especially artificial airways) are long and narrow. Estimates of lung delivery of aerosolized surfactants with most conventional delivery systems have been generally less than 1–10% of amount the liquid surfactant placed in the nebulizer.
However, animal work with improved aerosol delivery systems has shown some promise of increased efficiency. The gas exchange and mechanical benefits that have been seen in animal lung models with the aerosol approach were comparable to those seen with the instillation technique, but those benefits were achieved with only a fraction of the conventional 100 mg/kg of body weight (BW) instilled dose (MacIntyre, N. R., “Aerosolized Medications for Altering Lung Surface Active Properties”. Respir Care 2000;45(3) 676–683). As an example of improved aerosol delivery methods in the prior art, increased deposition of aerosolized surfactant has been achieved in animal models using ultrasonic nebulizers instead of jet nebulizers. Lung surfactant deposition of only 0.15–1.6 mg/kg BW/hour has been reported using jet nebulization, whereas deposition of about 10 mg/kg BW/hour (7–9 mg/kg BW with 50 minute nebulization) has been achieved with ultrasonic nebulization. See, for example, Schermuly R et al; “Ultrasonic Nebulization for Efficient Delivery of Surfactant in a Model of Acute Lung Injury—Impact on Gas Exchange.” Am. J. Respir. Crit. Care Med.; 1997 156 (2) 445–453.
It has been reported that respiratory support with nasal continuous positive airway pressure (“nCPAP”) systems, coupled with early instillation of lung surfactants, may have several advantages in the treatment of neonates with iRDS. This treatment has been found to be effective in decreasing the need for mechanical ventilation, with its accompanying mechanical and infectious risks and pathophysiological effects, but still requires intubation for surfactant treatment. See, for example, “Early Use of Surfactant, NCPAP Improves Outcomes in Infant Respiratory Distress Syndrome”; Pediatrics 2004; 11;e560–e563 (as reported online by Medscape Medical News group, Jun. 4, 2004).
Opportunities for aerosol delivery of lung surfactants to infants weighing less that 5 kg. have been limited, largely due to the low minute volumes required and the relatively high flow rates of nebulizers and ventilatory support devices that have been available. It has been demonstrated that pre-term infants, both on and off the ventilator, received less than 1% of the nebulizer dose to their lungs. See “Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia”. Pediatr. Pulmonol. 1996 May;21; (5):301–9. There has been little empirical data to suggest that nCPAP would be any more efficient since most animal and in vitro CPAP models have demonstrated less than 3% deposition.
Simultaneous administration of surfactant aerosol therapy (using a jet nebulizer) in conjunction with a CPAP system has been found to be clinically feasible and to result in improved respiratory parameters. See, for example, Jorch G et al; “To the Editor: Surfactant Aerosol Treatment of Respiratory Distress Syndrome in Spontaneously Breathing Premature Infants”; Pediatric Pulmonology 24:22–224 (1997); and Smedsaas-Lofvenberg A; “Nebulization of Drugs in a Nasal CPAP System”; Acta Paediatr 88: 89–92 (1999). However, the losses of aerosolized lung surfactant and other aerosolized medicaments used in CPAP systems were found to be unacceptably high, mainly because of the continued inefficiency of the delivery system. The authors suggest that as much as 10% of the nebulized surfactant might be expected to enter the pharyngeal tube coupled to the patient's respiratory system, but they did no testing to quantify that delivery estimate. (Jorch G et al, supra).
A number of studies have tried to combine aerosolized surfactant with high-frequency ventilation of the infant with iRDS, and aerosolized surfactants have also been tried in the treatment of airway diseases, e.g. cystic fibrosis and chronic bronchitis, both with mixed success, again because of the inefficiency of the delivery systems used. (McIntyre, supra).
As can be seen by the foregoing discussion, many important respiratory therapies for the treatment of lung surfactant deficiency or dysfunction have not been cost-effective or practical to pursue due to the inefficiencies of existing aerosol delivery technology. The present invention is directed to a method of treating these diseases through improved aerosol generation and delivery.